Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS (Dagani, Chem. Eng. News, Nov. 23, 1987 pp. 41-49) involve administration of compounds such as 2',3'-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-b-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide, 3'-azido-3'-deoxythymidine, and adriamycin that inhibit viral DNA synthesis; compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and compounds which treat the opportunistic infections caused by the immunosupression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotension converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. However, no therapeutically useful renin protease inhibitors have been developed, due to problems of oral availability and in vivo stability. The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98, 1 (1988). Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol. 53, 899 (1985); Katoh et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive possible target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
Moore, Biochem. Biophys. Res. Commun., 159 420 (1989) discloses peptidyl inhibitors of HIV protease. Erickson, European Patent Application No. WO 89/10752 discloses derivatives of peptides which are inhibitors of HIV protease.
U.S. Pat. No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases. U.S. Pat. No. 4,644,055 discloses halomethyl derivatives of peptides as inhibitors of viral proteases. European Patent Application No. WO 87/07836 discloses L-glutamic acid gamma-monohydroxamate as an antiviral agent.
The ability to inhibit a protease provides a method for blocking viral replication and therefore a treatment for diseases, and AIDS in particular, that may have fewer side effects when compared to current treatments. The topic of this patent application is 1,4-dimino-2,3-dihydroxybutanes and the development of processes for the preparation of these diols which compounds are capable of inhibiting viral protease and which compounds are believed to serve as a means of combating viral diseases such as AIDS. The diols of this invention provide significant improvements over protease inhibitors that are known in the art. A large number of compounds have been reported to be renin inhibitors, but have suffered from lack of adequate bio-availability and are thus not useful as therapeutic agents. This poor activity has been ascribed to the unusually high molecular weight of renin inhibitors, to inadequate solubility properties, and to the presence of a number of peptide bonds, which are vulnerable to cleavage by mammalian proteases. The diols described herein have a distinct advantage in this regard, in that many do not contain peptide bonds, are of low molecular weight, and can be hydrophilic yet still inhibit the viral protease enzyme.
Additionally, many compounds that inhibit renin do not inhibit HIV protease. The structure-activity requirements of renin inhibitors differ from those of HIV protease inhibitors. The diols of the invention are particularly useful as HIV protease inhibitors.
Other HIV protease inhibitors have been reported, but to date very few have shown activity against viral replication in human cells. This lack of cellular activity is probably due to the factors discussed above for renin inhibitors. Unlike other HIV protease inhibitors, diols disclosed herein show potent inhibition of viral replication in human cells.
An additional advantage of the diols disclosed herein is that some of them are symmetrical. The symmetrical diols may offer improved binding potency to the HIV protease enzyme relative to dissymmetric counterparts, and are more readily prepared from inexpensive starting materials.
The 1,2-diol unit is one of the most ubiquitous functional groups in nature, and consequently a wealth of methods leading to its synthesis have been developed. Foremost in this arsenal are the catalytic osmylation of olefins (Behrens and Sharpless, J. Org. Chem., (1985), 50, 5696), ring opening of epoxides (Wai et al., J. Am. Chem. Soc. (1989), 111, 1123), reduction or alkylation of a-hydroxy/alkoxy carbonyls (Davis et al., J. Org. Chem., (1989), 54, 2021). Common to all of these approaches is the preexistence of the central carbon-carbon bond of the diol function. Methods that lead directly to a 1,2-diol via formation of this bond are less common and include the reaction of an a-alkoxy anion (Cohen and Lin, J. Am. Chem. Soc., (1984), 106, 1130), with a carbonyl, and the reductive coupling of two carbonyls (i.e., pinacol coupling) (Pons and Santelli, Tetrahedron, (1988), 44, 4295).
Of all these methods, pinacol coupling is conceptually one of the simplest methods for the synthesis of 1,2-diols. Consequently, a number of methods have been developed which utilize this reaction for the preparation of these compounds. For example, McMurry et al., report the preparation of a 1,2-diol by pinacol coupling of a dialdehyde in the presence of TiCl.sub.3 (dimethoxyethane).sub.2 Zn-Cu in dimethoxyethane (McMurry et al., Tetrahedron Lett., (1988), 30, 1173). In a recent review article, Pons and Santelli describe many other methods leading to 1,2-diols which rely on low valent titanium complexes (Pons and Santelli, Tetrahedron, (1988), 44, 4295). Finally, Freudenberger et al., J. Am. Chem. Soc., (1989), 111, 8014-8016 disclose a method which utilizes a vanadium (II) complex, [V.sub.2 C.sub.13 (THF).sub.6 ].sub.2 [ZN.sub.2 Cl.sub.6 ] to couple aldehydes.
While these methods are generally useful for the preparation of 1,2-diols, none of these teach how amino moieties can be incorporated into the diols. Furthermore, none of the methods disclosed in the prior art teach to make four stereocenters in a selective manner.
EP 402 646 discloses retroviral protease inhibiting compounds of the formula: A-X-B where A and B are independently substituted amino, substituted carbonyl, functionalized imino, functionalized alkyl, functionalized acyl, functionalized heterocyclic or functionalized (heterocyclic) alkyl and X is a linking group.